PROVISIONAL PEER-REVIEWED TOXICITY VALUES for N-HEPTANE (CASRN 142-82-5)

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United States EPA/690/R-16/003F Environmental Protection Final Agency 9-08-2016 Provisional Peer-Reviewed Toxicity Values for n-Heptane (CASRN 142-82-5) Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 AUTHORS, CONTRIBUTORS, AND REVIEWERS CHEMICAL MANAGER Lucina E. Lizarraga, PhD National Center for Environmental Assessment, Cincinnati, OH CONTRIBUTORS Q. Jay Zhao, MPH, PhD, DABT National Center for Environmental Assessment, Cincinnati, OH Scott C. Wesselkamper, PhD National Center for Environmental Assessment, Cincinnati, OH DRAFT DOCUMENT PREPARED BY SRC, Inc. 7502 Round Pond Road North Syracuse, NY 13212 PRIMARY INTERNAL REVIEWERS J. Phillip Kaiser, PhD, DABT National Center for Environmental Assessment, Cincinnati, OH Ghazi Dannan, PhD National Center for Environmental Assessment, Washington, DC This document was externally peer reviewed under contract to: Eastern Research Group, Inc. 110 Hartwell Avenue Lexington, MA 02421-3136 Questions regarding the contents of this PPRTV assessment should be directed to the EPA Office of Research and Development’s National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300). ii n-Heptane TABLE OF CONTENTS COMMONLY USED ABBREVIATIONS AND ACRONYMS .................................................. iv BACKGROUND .............................................................................................................................1 DISCLAIMERS ...............................................................................................................................1 QUESTIONS REGARDING PPRTVs ............................................................................................1 INTRODUCTION ...........................................................................................................................2 REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) ..............4 HUMAN STUDIES .................................................................................................................... 9 Oral Exposures ........................................................................................................................ 9 Inhalation Exposures ............................................................................................................... 9 ANIMAL STUDIES ................................................................................................................. 10 Oral Exposures ...................................................................................................................... 10 Inhalation Exposures ............................................................................................................. 12 OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) ................................ 15 Genotoxicity .......................................................................................................................... 15 Supporting Human Toxicity Studies ..................................................................................... 16 Supporting Neurotoxicity Studies in Animals ...................................................................... 16 Acute Systemic Toxicity in Animals .................................................................................... 16 Absorption, Distribution, Metabolism, and Elimination (ADME) Studies .......................... 17 Mode-of-Action/Mechanistic Studies ................................................................................... 19 DERIVATION OF PROVISIONAL VALUES ............................................................................20 DERIVATION OF ORAL REFERENCE DOSES .................................................................. 20 DERIVATION OF INHALATION REFERENCE CONCENTRATIONS ............................. 21 Derivation of a Subchronic Provisional Reference Concentration (p-RfC) ......................... 23 Derivation of a Chronic Provisional Reference Concentration (p-RfC) ............................... 25 CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR ............................................................ 27 DERIVATION OF PROVISIONAL CANCER POTENCY VALUES ................................... 28 APPENDIX A. SCREENING PROVISIONAL VALUES ...........................................................29 APPENDIX B. DATA TABLES ...................................................................................................42 APPENDIX C. BENCHMARK DOSE MODELING RESULTS ................................................48 APPENDIX D. REFERENCES .....................................................................................................56 iii n-Heptane COMMONLY USED ABBREVIATIONS AND ACRONYMS α2u-g alpha 2u-globulin MN micronuclei ACGIH American Conference of Governmental MNPCE micronucleated polychromatic Industrial Hygienists erythrocyte AIC Akaike’s information criterion MOA mode of action ALD approximate lethal dosage MTD maximum tolerated dose ALT alanine aminotransferase NAG N-acetyl-β-D-glucosaminidase AST aspartate aminotransferase NCEA National Center for Environmental atm atmosphere Assessment ATSDR Agency for Toxic Substances and NCI National Cancer Institute Disease Registry NOAEL no-observed-adverse-effect level BMD benchmark dose NTP National Toxicology Program BMDL benchmark dose lower confidence limit NZW New Zealand White (rabbit breed) BMDS Benchmark Dose Software OCT ornithine carbamoyl transferase BMR benchmark response ORD Office of Research and Development BUN blood urea nitrogen PBPK physiologically based pharmacokinetic BW body weight PCNA proliferating cell nuclear antigen CA chromosomal aberration PND postnatal day CAS Chemical Abstracts Service POD point of departure CASRN Chemical Abstracts Service Registry PODADJ duration-adjusted POD Number QSAR quantitative structure-activity CBI covalent binding index relationship CHO Chinese hamster ovary (cell line cells) RBC red blood cell CL confidence limit RDS replicative DNA synthesis CNS central nervous system RfC inhalation reference concentration CPN chronic progressive nephropathy RfD oral reference dose CYP450 cytochrome P450 RGDR regional gas dose ratio DAF dosimetric adjustment factor RNA ribonucleic acid DEN diethylnitrosamine SAR structure activity relationship DMSO dimethylsulfoxide SCE sister chromatid exchange DNA deoxyribonucleic acid SD standard deviation EPA Environmental Protection Agency SDH sorbitol dehydrogenase FDA Food and Drug Administration SE standard error FEV1 forced expiratory volume of 1 second SGOT glutamic oxaloacetic transaminase, also GD gestation day known as AST GDH glutamate dehydrogenase SGPT glutamic pyruvic transaminase, also GGT γ-glutamyl transferase known as ALT GSH glutathione SSD systemic scleroderma GST glutathione-S-transferase TCA trichloroacetic acid Hb/g-A animal blood-gas partition coefficient TCE trichloroethylene Hb/g-H human blood-gas partition coefficient TWA time-weighted average HEC human equivalent concentration UF uncertainty factor HED human equivalent dose UFA interspecies uncertainty factor i.p. intraperitoneal UFH intraspecies uncertainty factor IRIS Integrated Risk Information System UFS subchronic-to-chronic uncertainty factor IVF in vitro fertilization UFD database uncertainty factor LC50 median lethal concentration U.S. United States of America LD50 median lethal dose WBC white blood cell LOAEL lowest-observed-adverse-effect level iv n-Heptane FINAL 09-08-2016 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR n-HEPTANE (CASRN 142-82-5) BACKGROUND A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant scientific literature using established Agency guidance on human health toxicity value derivations. All PPRTV assessments receive internal review by a standing panel of National Center for Environment Assessment (NCEA) scientists and an independent external peer review by three scientific experts. The purpose of this document is to provide support for the hazard and dose-response assessment pertaining to chronic and subchronic exposures to substances of concern, to present the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to characterize the overall confidence in these conclusions and toxicity values. It is not intended to be a comprehensive treatise on the chemical or toxicological nature of this substance. The PPRTV review process provides needed toxicity values in a quick turnaround timeframe while maintaining scientific quality. PPRTV assessments are updated approximately on a 5-year cycle for new data or methodologies that might impact the toxicity values or characterization of potential for adverse human health effects and are revised as appropriate. It is important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current information available. When a final Integrated Risk Information System (IRIS) assessment is made publicly available on the Internet (http://www.epa.gov/iris), the respective PPRTVs are removed from the database. DISCLAIMERS The PPRTV document provides toxicity values and information about the adverse effects of the chemical and the evidence on which the value is based, including the strengths and limitations of the data. All users are advised to review the information provided in this document to ensure
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